Ghigf I Axis Proteins

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 Ghigf I Axis Proteins Background

Growth in vertebrates is governed by the integration of genetic, hormonal, and nutritional components. The most significant endocrine influence in body growth is the complex regulation of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis, and this mechanism appears to be highly conserved among vertebrates. Growth hormone is involved in regulating numerous physiological processes besides somatic growth in fish including immune function, lipid and protein metabolism, osmoregulation, and feeding behavior. In teleost fish, secretion of GH from the pituitary is regulated by sex steroids along with several hypothalamic factors, which act in concert under the influence of the physiological and nutritional state of the animal.

Growth hormone acts directly on target tissue by stimulating mitosis, and indirectly by initiating the production and release of IGF-I, a mitogenic factor produced primarily in the liver. The physiological actions of GH are mediated through its binding to the growth hormone receptor (GH-R), located on the surface of cells in target tissue. We have recently identified two GH-R subtypes (GH-R1 and -R2) in the Mozambique tilapia, one of which (GH-R1) we believe to be the putative receptor for somatolactin (SL-R) and the other (GH-R2), the growth hormone-receptor (GH-R). Somatolactin (SL) is a member of the GH/prolactin family of pituitary peptide hormones, which is present in a variety of teleost species as well as the sturgeon and lungfish, but not in tetrapods. The signal transduction by the GH-R leads to the biological actions evoked by GH. Protein restriction during fasting has been shown to reduce circulating IGF-I and liver IGF-I mRNA levels in several teleost species including the tilapia. Alterations in circulating GH and IGF-I due to disruptions in metabolic rhythms in turn alter the number and post-receptor functions of GH-R through changes in the transcription and translation of the GH-R. Insulin-like growth factor-II (IGF-II) shares a high structural homology with IGF-I, and gene expression of both mitogens appears to be regulated in fish in several tissue types by GH. In contrast with mammals which express IGF-II chiefly during embryonic development, IGF-II is expressed widely in both juvenile and adult fish. On the other hand, the metabolic actions of IGF-II in fish are virtually unknown. Both IGFs also activate cell proliferation suggesting that they share several overlapping physiological roles in fish.


Effects of fasting and re-feeding on GH/IGF-I axis in fish

There have been numerous studies of the effects of partial or total nutrient restriction on the GH/IGF-I axis in teleost fish. One of the first comprehensive studies on the subject was designed to address the mechanisms that underlay growth hormone resistance. This laid the groundwork for future experiments that sought to understand the seemingly contradictory findings that elevated plasma GH in fish is not necessarily correlated with increased growth rate. Instead, increased binding of GH to its hepatic receptor is strongly correlated with seasonal increases ingrowth, regardless of changes in circulating GH. Furthermore, a GH-induced catabolic state during fasting is associated with many factors including lowered circulating and hepatic expression of IGF-I, along with decreased hepatic GH-R binding in the presence of elevated plasma GH. A dose-related decrease in plasma GH, accompanied by concurrent increases in plasma IGF-I and hepatic GH binding sites was shown to occur in sea bream fed increasing dietary protein levels. A subsequent fasting study was conducted to characterize the effects of varying ration levels on plasma GH, specific growth rate, and various other growth-related endocrine factors. The authors observed an increase in plasma GH associated with decreased ration size, but failed to see a correlation between plasma GH levels and specific growth rate.

Interestingly, Menton et al. (2000) observed a decline in IGF-I mRNA levels following a period of fasting in the sea bream that recovered upon re-feeding. On the other hand, they saw no effect of dietary protein levels on IGF-I mRNA transcript levels. The authors also observed no correlation between body growth and hepatic IGF-I mRNA levels. Similarly, food deprivation was shown to increase plasma GH in the goldfish, while subsequent re-feeding reversed the effects. Replacement of fishmeal with plant-derived protein sources in feed produced a significant increase in plasma GH and a decrease in plasma IGF-I following an overnight fast in sea bream. Likewise, fasting resulted in an elevation in plasma GH and a decrease in plasma and hepatic expression of IGF-I in Chinook salmon. Plasma GH increased, while plasma IGF-I and hepatic expression of IGF-I and GH-R decreased in fasted coho salmon. Fasted rainbow trout exhibited also elevated plasma GH and suppressed plasma IGF-I with reduced IGF-I mRNA in liver and muscle. Fasting also resulted in lowered GHR1 (SL-R), but not GH-R2 (GH-R) mRNA levels in liver and muscle tissue. Re-feeding resulted in a normalization of plasma GH and IGF-I to fed control levels. Hepatic and muscle expression of IGF-I and GH-R1 mRNA also returned to levels of fed control fish, while expression of GH-R2 (GH-R) increased following refeeding in liver and muscle. In the grouper, fasting brought about an elevation of pituitary expression of GH mRNA, while at the same time reduced hepatic IGF-I mRNA. Subsequent re-feeding resulted in a restoration of the expression of both genes to fed control levels. Interestingly, pituitary expression of GH mRNA increased in the rabbitfish during fasting along with a transient increase in hepatic expression of IGF-I. Following re-feeding, pituitary GH mRNA levels returned to those of fed controls, and expression of hepatic IGF-I mRNA fell transiently below control values.

These results indicate that the up-regulation of plasma GH in parallel with decreased plasma IGF-I and liver expression of IGF-I mRNA represent a conserved mechanism in teleost and vertebrate evolution in general. This physiological state of “GH-resistance” shifts metabolism in favor of mobilizing stored substrates to maintain energetic homeostasis instead of promoting tissue growth.

Mozambique tilapia is known to grow faster in seawater than in fresh water. Nevertheless, previous studies of the effects of fasting have been restricted to the study of fish acclimated to fresh water. In view of the fact that GH plays an important role in seawater acclimation in several euryhaline fishes including the tilapia, fasting in seawater may affect the GH/IGF-I axis of the tilapia more profoundly than in the fish in fresh water.